Gurren Lagann takes place in a future where Earth is ruled by the Spiral King, Lordgenome, who forces mankind to live in isolated subterranean villages. These villages have no contact with the surface world or other villages and are under constant threat of earthquakes. Selected villagers called diggers are conscripted to expand their homes deeper underground. Simon, a meek young digger ostracized by his peers, finds solace in his best friend and older brother figure, an eccentric delinquent named Kamina. Kamina encourages Simon to join his gang, Team Gurren, to help him achieve his dream of visiting the surface world. One day, Simon unearths a drill-shaped key called a Core Drill, followed by a small mecha resembling a face called a Gunmen.^[10][11]Shortly thereafter, a huge Gunmen crashes through the ceiling and begins attacking the village, followed by a girl named Yoko, who attempts to repel the Gunmen. Simon uses his Core Drill to activate the smaller Gunmen (which Kamina names Lagann), and it is used to destroy the larger Gunmen and break through to the surface world.

Simon and Kamina learn from Yoko that humans on the surface are attacked each day by Gunmen piloted by beastmen, humanoid creatures who serve as Lordgenome's army. Kamina hijacks a Gunmen and names him Gurren, combining him with Lagann to form the mecha Gurren Lagann. Their actions inspire other humans to steal their own Gunmen and join Team Gurren, which makes Kamina rename it Team Dai-Gurren. Eventually Team Dai-Gurren captures an enemy Gunmen fortress to use as their base of operations, though Kamina is killed in the preceding battle by one of Lordgenome's four generals. Rossiu, a boy from another village, takes over the job of piloting Gurren, but Kamina's death causes Simon to sink into depression until he meets Nia, Lordgenome's daughter. Team Dai-Gurren is initially distrustful of her but allows her to join when it becomes apparent that she was abandoned by her father, like many who came before her. Nia helps Simon come to terms with Kamina's death, and the rest of Team Dai-Gurren prompt him to take up the role as the team's leader, leading them and other humans, who captured other Gunmen and Gunmen fortresses, to Lordgenome's palace. As the palace itself turns out to be a gigantic Gunmen called the Lazengann and launches armies of other Gunmen, the human forces hold them off while Simon, Nia, and Rossiu pilot Gurren Lagann against Lordgenome, who fights them in a similar Gunmen. When both Gunmen are damaged, he himself fights Simon in Lagann with his bare hands. Lordgenome emerges victorious, until Simon uses his Core Drill to defeat him once and for all.

Over the next seven years, mankind prospers on the surface world with Simon and the members of Team Dai-Gurren serving as the world's government. As soon as the world's population reaches one million people, an alien race called the Anti-Spirals emerges and uses Nia to announce the Moon's collision with Earth, which will wipe out all life on the planet and prevent them from evolving to such an extent that they will risk destroying the universe in a cataclysmic event called the Spiral Nemesis. With guidance from Lordgenome resurrected as a bio-computer, who was once part of an intergalactic group of warriors who fought the Anti-Spirals and had hidden mankind underground to protect them from the Anti-Spirals, and with help from Viral, an old enemy of Simon who pilots Gurren, Simon, Gurren Lagann and Team Dai-Gurren prevent the Moon's collision, revealing it to be Lordgenome's flagship that was reprogrammed by the Anti-Spirals. Using it, they retrieve the real Moon from the pocket dimension where the Anti-Spirals had hidden it and go to the Anti-Spiral homeworld, where after significant loss, they rescue Nia, and after a battle that spans the universe, Simon in Lagann finally destroys the Anti-Spirals. This, however, causes Nia to fade away and die as her own existence is tied to that of the Anti-Spirals. Simon then spends the rest of his life wandering the planet as a nameless vagrant while his comrades set out to work with other races throughout the galaxy to help prevent the Spiral Nemesis and ensure the safety of the universe.